Pharmacodynamics and pharmacokinetics of ticagrelor vs. clopidogrel in patients with acute coronary syndromes and chronic kidney disease

Abstract

Background: Pivotal clinical trials found that ticagrelor reduced ischaemic complications to a greater extent than clopidogrel, and also that the benefit gradually increased with the reduction in creatinine clearance. However, the underlying mechanisms remains poorly explored.

Methods: This was a single-centre, prospective, randomized clinical trial involving 60 hospitalized Adenosine Diphosphate (ADP) P2Y12 receptor inhibitor-naïve patients with chronic kidney disease (CKD) (estimated glomerular filtration rate <60 ml min^-1 1.73 m^-2 ) and non-ST-elevation acute coronary syndromes (NSTE-ACS). Eligible patients were randomly assigned in a 1:1 ratio to receive ticagrelor (180 mg loading dose, then followed by 90 mg twice daily) or clopidogrel (600 mg loading dose, then followed by 75 mg once daily). The primary endpoint was the P2Y12 reactive unit (PRU) value assessed by VerifyNow at 30 days. The plasma concentrations of ticagrelor and clopidogrel and their active metabolites were measured in the first 10 patients in each group at baseline, and at 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after the loading dose.

Results: Baseline characteristics were well matched between the two groups. Our results indicated a markedly lower PRU in patients treated with ticagrelor vs. clopidogrel at 30 days (32.6 ± 11.29 vs. 203.7 ± 17.92; P < 0.001) as well as at 2 h, 8 h and 24 h after the loading dose (P < 0.001). Ticagrelor and its active metabolite AR-C124910XX showed a similar time to reach maximum concentration (C_max ) of 8 h, with the maximum concentration (C_max ) of 355 (242.50-522.00) ng ml^-1 and 63.20 (50.80-85.15) ng ml^-1 , respectively. Both clopidogrel and its active metabolite approached the C_max at 2 h, with a similar C_max of 8.67 (6.64-27.75) ng ml^-1 vs. 8.53 (6.94-15.93) ng ml^-1 .

Conclusion: Ticagrelor showed much more potent platelet inhibition in comparison with clopidogrel in patients with CKD and NSTE-ACS.

Keywords: chronic kidney disease; non-ST-elevation acute coronary syndromes; pharmacodynamics; ticagrelor.

Figure 1

Flow chart of the COmparison of The Pharmacodynamics and pharmacokinetics of Ticagrelor vs. clopidogrel in patients with non–ST‐elevation acute coronary syndromes and Chronic Kidney Disease (OPT‐CKD) trial. Eligible patients were randomly assigned in a 1:1 ratio to receive ticagrelor or clopidogrel (R 1:1). ASA, aspirin; CKD, chronic kidney disease; CLO, clopidogrel; CYP, cytochrome P450; eGFR, estimated glomerular filtration rate; HPR, high on‐treatment platelet reactivity; IPA, inhibition of platelet aggregation; LD, loading dose; NSTE‐ACS, non‐ST‐elevation acute coronary syndromes; PRU, platelet reactive unit; qd, once daily; TIC, ticagrelor *Plasma concentrations of clopidogrel, clopidogrel active metabolite‐derivatized (CAMD), ticagrelor and its active metabolite AR‐C124910XX were assessed predose and 1, 2, 4, 8, 12 and 24 h after the loading dose

Figure 2

Platelet reaction units (A) and inhibition of platelet aggregation (B) by protocol time and treatment. Data are expressed as mean ± standard error *P < 0.001, ticagrelor vs. clopidogrel

Figure 3

Correlation between baseline estimated glomerular filtration rate (eGFR) (A) and cytochrome B450 2C19 genotype (B) and 30‐day inhibition of platelet aggregation in non‐ST‐elevation acute coronary syndromes patients with chronic kidney disease. EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer

Figure 4

Overview of clopidogrel and ticagrelor pharmacokinetics on day 1. Plasma concentrations of clopidogrel (A), clopidogrel active metabolite‐derivatized (CAMD) (B), ticagrelor (C) and its active metabolite AR‐C124910XX (D) were measured before and 1–24 h after the administration of a loading dose of 600 mg clopidogrel or 180 mg ticagrelor. Maximum concentration (C _max) and time to reach C _max (T _max) were established directly from the measured plasma concentration of each patient and presented as medians with interquartile range. Individual data are also shown, and the pharmacokinetic trend was demonstrated via the connecting curves of mean values